Process for the manufacture of alpha, beta-unsaturated ketones of the cyclopentano polyhydro phenanthrene series



- Patented July15, 1941 UNITED STATES PATENT oi-P ca; I w PROCESS FORTHiffiIiiIFACTURE Oi? afi- UNSATURATED KETONES PENTANO POLYHYDRO SERIESOF THE cYcLo- PHENANTBRENE Adolf Butenandt, Berlin-Lichterfelde,Germany,

assignor to Schering Corporation, N. 'J., a corporation of New Jersey NoDrawing. Application March 26, 1937, Serial No. 133,204. In GermanyMarch 31, 1936 (01. zen-397.3)

16 Claims.

"lhis .;invention.relatesto a process for the manufacture .orens-unsaturated ketones of the cyclopentano polyhydro phenanthreneseries of the general formula C19H260(X) and the constitutional formula:

CH CH3 /\/W/ J v\/ in, which X indicates H R R r Y Y H Y being ahydroxyl group or a group convertible into the hydroxyl group byhydrolysis, as, for example, an ester or ether group or the like and Rindicates any suitable substituted or nonsubstituted hydrocarbonresidue. In particular there is involved in the present invention aprocess for the manufacture of nap-unsaturated ketones of the androstaneseries, the pregnane series and also the sterol and bile acid series.

.The process of manufacture according to the invention consists in thatthe fin-unsaturated ketones of the cyclopentano polyhydro phenanthreneseries of the same general formula CinH2sO(X) and the constitutionalformula:

C H; CH3

X having the abovesignification, are subjected to a treatment which hasfor its efiect the displacement of a carbon-carbondouble bond inay-unsaturated ketones.

The reagents and reaction conditions suitable for the production of suchan intramolecular re are gently heated for a short time in acid oralkaline solution, say in alcohol with the addition ofdilute mineralacid or dilute alkali lye;

on working up the reaction solution there is then obtained directly inpractically quantitative yield the rearranged nap-unsaturated ketone.

It is also possible, liowever,'for the. purpose of displacement of thecarbon-carbon double bond to proceed in such a manner that in the firstplace halogen hydride, for example, hydrogen chloride is added on to thefin-unsaturated ketones and then from the addition product formed, bytreatment of the same with alkaline reacting agents halogen hydrideagain split off.

In a similar manner from flay-unsaturated ketones likewise thecorresponding aid-unsavurated keytones are obtained when there is added1 on to the p.'y-unsaturated ketones halogen, for,

example, bromine, and then from the dihalogen compound formed thehalogen again split oil. by means of zinc or the like in an acid medium.

Also the heating of the pry-unsaturated ketones with or without solventsto elevated temperatures, for example, to their melting point, leads tothe isomerisation.

Further as contact substances finely dividedmetals or metal compounds,as, for example, nickel, platinum, aluminium oxide and the like can beemployed. for the intramolecular rearrangement of pay-unsaturatedketones to nap-unsaturated'ketones. 1 r

- The ,d'y-unsaturat'ed-ketones' of the cyclopen tano polyhydrophenanthrene series coining into consideration for the presentisome'l'ilsatlon process can be produced in anyfsuitable manner. Onemethod of manufacture of such pay-unsaturated ketones consistAer-example, in that the corr'fiofidifiidihalgen compounds of theketenes, in particular the dibromo compounds, arev dehalogenated byshort heating with zinc dust in ethanol or methanol, that isto saytherefore in a neutral medium as is described in specifiarrangement aredescribed among others in Houben-Weyl, Methoden der organischen Chemie,vol. 2, 2nd edition (-1922), page 470 et seq. and page 756 et seq:

Thus, it is easily possible, for example, to convert the fro-unsaturatedketones into the corresponding mil-unsaturated ketones when they theyare either themselves I Example 1 26 mg. of As-cholestenone-(3) aredissolved in 3.5 ccs. of methanol, treated with 3 drops of 4 N sulphuricacid (about 0.05 ccs.) and heated on the water bath for 5 minutes, thesolution at the same time being evaporated to about one half.

On cooling the A4-ch0lestenone-(3) crystallises in long needles ofmelting point 80 C. The yield amounts to 20 mg.

Instead of methanol also ethanol or glacial acetic acid with a few dropsof mineral acid, for example, dilute sulphuric acid, hydrochloric orhydrobromic acid and the like can be employed.

Example 2 i mg. of At-cholestenone-(ti) are dissolved in 0.5 cos. ofethanol with the addition of 2 drops of 2 N caustic soda lye; thesolution which becomes yellow colored after the addition of the causticsoda lye is heated for 5 minutes on the water bath and thereupon aftercooling carefully sprayed with water. In a yield of 8 mg. is thenobtained the A4-cholestenone-(3) in the form of long needles of meltingpoint 80 C.

Example 3 3.8 mg. of As-pregnendione-(320) are dissolved in the hot inthe smallest quantity of alcohol and after the addition of 1 drop ofabout alcoholic aqueous sulphuric acid, heated for 6 minutes on thewater bath. After cooling cold water is introduced to the commencementof turbidiflication and the solution seeded with A4- pregnendione-(320)in the form of the so-called ii-progesterone of melting point 121 C.There are then obtained in'a yield of 3.4 mg. the characteristic longneedles of fi-progesterone of melting point 121 C.

The needle shaped crystal modification of the A4-pregnendione-(320)obtained can be converted by dissolving in hot alcohol, spraying withhot water and seeding with A4-pregnendione-(320) in the form of theso-called lat-progesterone of melting point 128.5 0., into the prismshaped crystal modification of melting point 128.5 C. On taking a mixedmelting point of the so-called A4pregnendione-(3.20) with the natural0:- progesterone isolated from corpera lutea no lowering of the meltingpoint of 128.5 C. takes place.

Example 4 5.25 mg. of pure As-pregnendione-(320) of melting point 158 to160 C. are heated for about 8 minutes to 160 C. There is obtained aslightly yellow-colored product, which compared with the specificrotation of the starting material of in chloroform exhibits an increaseof the rotation value to a thereby indicating the formation ofAvpregnendime-(3.20) with the specific rotation l lt +194 Example 5Example 6 30 mg. of A5-1'l-ethyl-androstenol-(l'l)-one- (3) of meltingpoint 149 C. are dissolved in 0.5 ccs. of alcohol and heated for 5minutes on the water bath with the addition of 1 drop of 4, N

sulphuric acid. Thereupon the solution is carefully sprayed with waterin the cold; slowly well formed leaflets crystallise of M. P. 136 C.which apparently contain water of crystallisation. On recrystallisationof these crystals from petrol ether of boiling poi'n't'l0-80" C. themelting point increases to 139 C. On the basis of the analysis 1 valuesthe Ai-ethyl-androstenol-(1'7) one-(3) in this form is present in pure,anhydrous condition.

The m-ethyl-androstenol-(l'l)-one-(3) yields on reaction withsemicarbazide acetate in alcoholic solution a semicarbazone which afterrecrystallisation from dilute methanol exhibits a melting point of 230C. with decomposition.

Example 7 32 mg. of As-cholestenone-(3) in 4 cos. of glacial acetic acidare treated with an equimo- -lecular quantity of bromine. From thesolution which soon becomes decolorised, by the addition of waterthe5.6-dibromo-cholestenone formed is precipitated; it exhibits afterrecrystallisation from acetone a melting point of C.

20 mg. of 5.6-dibromo-cholestenone are dissolved in 3 cos. of methanoland after theaddi- ,tion of 4 drops of a 5 N sulphuric acid heated with20 mg. of zinc dust for 10 minutes with shaking on the water bath. Fromthe solution filtered from zinc dust is obtained on evaporation in ayield 01'15 mg. the A45-cholestenone-(3) of melting point 80 C.

The same result is also obtained by debromina- .tion with zinc inacidified ethanol.

Example 8 Y water and extracted with ether: from the ethereal solutionwashed free from acid are then obtained about 2 mg. ofA4-pregnendione-(320) of melting point 128 C.

Example 9 10 mg. of As-andrcstenol-(l'l)-one-3-acetate' are dissolved in2 cos. of methanol, treated with 2 drops of 5 N hydrochloric acid andsprayed with warnf water. There crystallise 1on8 needles of M. P. 138'C. A mixed melting point test with testosterone acetate save nodepression.

Of course, many changes and variations in the reaction conditions andthe like may he,=-made. by those skilled in the art in accordance withthe principles set forth herein and in the claims annexed hereto.

What I claim is:

1. Process for the manufactu're'of a-p-unsaturated ketones of thecyclopentano polyhydro phen threne series, wherein aw-unsaturatedketones of the cyclopentano polyhydro phenanthrene series of thegeneralformulaCmHaO K and the constitutional formula CHs ICE: x

' dro phenanthrene compound to the action of an As.-pregnendione-.(3,20)with an acid to eifect displacement of the carbon-carbon double bond.

'1. Process for the manufacture of cap-unsaturated ketones oi thecyclopentano polyhydro phenanthrene series, which comprises treating aAs-pregnendione-(3,20) with a base to eflect displacement of thecarbon-carbon double bond.

8. Process for the manufacture of a.p-unsat-. urated ketones of thecyclopentano polyhydro phenanthrene series, which comprises heating aA5-pregnendione-(320) to elevated temperatures until displacement of thecarbon-carbon double bond is effected.

9. Process for the manufacture of a-p-unsaturated ketones of thecyclopentano polyhydro phenanthrene series comprising subjecting aAs,a-3-keto-l0,l3-dimethyl cyclopentano polyhyagency capable ofeffecting displacement of a carbon-carbon double bond in S -unsaturatedketones.

10. Process according tov claim 9 wherein the starting material is .a.As,s-3-keto-pre'gnene compound.

11. Process according to claim wherein the starting compound issubjected to elevated tem- I peratures in a non-neutral. medium untildisplacement of the double bond is effected.

12. Process for the manufacture of a.fi-.unsaturated ketones of thecyclopentano polyhydro phenanthrene series, which comprises-subjecting aA-10,l3-dimethyl cyclopentano polyhydro phenanthrene compound havingketonic oiwgen drocarbon radicals and oxygenated hydrocarbon radicals,are subjected to an agency capable of eifecting displacement of acarbon-carbon double bond in aw-unsaturated ketones to cause shifting ofthe double bond to the mil-position.

2; Process as claimed in claim 1, in which the displacement of thecarbon-carbon double bond in the pa -unsaturated ketone serving asstarting material is effected by means of acids.

3. Process as claimed in claim 1, in which the displacement of thecarbon-carbon double bond in the pry-unsaturated ketone serving asstarting material is effected by means of bases.

4. Process as claimed in claim 1. in which the displacement of thecarbon-carbon double bond in the azy-unsaturated ketone, serving asstarting material is efiected by heating the same with or withoutsolvent.

5. Process as claimed in claim 1, in which as starting material aA5-pregnendione-(320) is employed. s

6. Process for the manufacture of lap-unsaturated ketones of thecyclopentano polyhydro phenanthrene series, which comprises treating a adouble bond has been effected.

directly joined to the 3-carbon and having an oxygenated group at the17-p'osition, to the action ofan agency capable of effectingdisplacement-of the double bond into the 4',5-position.

13. Process according to claim 12, wherein the starting compound issubjected to the action of elevated temperatures until the shifting of14. Process according to claimlz, wherein the starting compound issubjected to the action of an acid until the shifting of the doublebondhas been eil'ected.

15. Process according to claim 12, wherein the starting compound issubjected to the action of a base until the shifting of the double bondhas been effected. 1

16. Process for the manufacture of tap-unsaturated ketones, of thecyclopentano polyhydro phenanthrene series, which comprises subjecting aA--10,13-dimethyl cyclopentano polyhydro phenanthrene compound havingketonic oxygen directly joined to the 3-carbon and having a ketonicgroup at the l'l-position, to the action of an agency capable ofeffecting displacement of the double bond into the 4,5-position.

ADOLF BUTENANDT.

